The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are
typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of
caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central
question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3
activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form
intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the
enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation
prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining...
[Ver más]
The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are
typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of
caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central
question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3
activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form
intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the
enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation
prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity
and subcellular localization.We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small
interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of
microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell
types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to
modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders.
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